There is little disagreement on the heritable component (the genetic origins) of autism. Identical twin studies[1] put it in a range between 0.36 and 0.957, with concordance for a broader phenotype usually found at the higher end of the range. Most studies confirm the heritability of autism with estimates well above 0.6 although one researcher claims lower heritabilities.[2]

Autism concordance in siblings and fraternal twins is anywhere between 0% and 23.5%. This is more likely 2%-4% for classic autism and 10%-20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population.

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Researchers usually note that autism is among the most heritable of all neurological conditions, even among the >90% of cases not associated with known genetic diseases such as fragile X syndrome or muscular dystrophy.[3]

Twin studies are a helpful tool in determining the heritability of disorders and low-prevalence human traits in general. They involve determining concordance of characteristics between identical (monozygotic or MZ) twins and between fraternal (dizygotic or DZ) twins. Possible problems of twin studies are: (1) errors in diagnosis of monozygocity, and (2) the assumption that social environment sharing by DZ twins is equivalent to that of MZ twins.

A condition that is environmentally caused without genetic involvement would yield a concordance for MZ twins equal to the concordance found for DZ twins. In contrast, a condition that is completely genetic in origin would theoretically yield a concordance of 100% for MZ pairs and usually much less for DZ pairs depending on factors such as the number of genes involved and assortative mating.

An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome (IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.[4] An
example of a human characteristics that is extremely heritable is eye color, with a concordance of 98% for MZ pairs and 7%-49% for DZ pairs depending on age.[5]

Notable twin studies that have attempted to shed light on the
heritability of autism are the following:

Folstein-Rutter (1977)

This small scale study was the first of its kind to look into the heritability of autism. It involved 10 DZ and 11 MZ pairs in which at least one twin in each pair showed infantile autism. It found a concordance of 36% in MZ twins compared to 0% for DZ twins. Concordance of "cognitive abnormalities" was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs discordant for autism, a biological hazard was believed to be associated with the condition.[How to reference and link to summary or text]

Wessels-Pompe-van Meerdervoort (1979)

This was a case report of a pair of identical twins concordant for autism. The twins developed similarly until the age of 4, when one of them spontaneously improved. The other twin, who had suffered infrequent seizures, remained autistic. The report noted that genetic factors were not "all important" in the development of the twins.[6]

Ritvo-Freeman-Mason-Brothers-Mo-Ritvo (1985)

This study of twins enrolled with the UCLA Registry for Genetic Studies found a concordance of 95.7% for autism in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.[7]

In this study, Nordic countries were screened for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins were examined. Concordance of autism was found to be 91% in MZ and 0% in DZ pairs. The concordances for "cognitive disorder" were 91% and 30% respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress.[8]

Bailey-Le-Couteur-Gottesman-Bolton-Simonoff-Yuzda-Rutter (1995)

The study reexamined a British twin sample and found 60% concordance for autism in MZ twins vs. 0% concordance for DZ. It also found 92% concordance for a broader spectrum in MZ vs. 10% for DZ. The study concluded that "obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors."[9]

Scourfield-Martin-Lewis-McGuffin (1999)

This study looked at social cognitive skills in general-population children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.[10]

Constantino-Todd (2000)

This study looked at reciprocal social behavior in general-population identical twins. It found a concordance of 73% for MZ, i.e. "highly heritable", and 37% for DZ pairs.[11]

Kates-Burnette-Eliez-Strunge-Kaplan-Landa-Reiss-Pearlson (2004)

This study looked at 16 MZ twins and found a concordance of 43.75% for "strictly defined autism". Neuroanatomical differences (discordant cerebellar white and grey matter volumes) between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader phenotype.[12]

Kolevzon-Smith-Schmeidler-Buxbaum-Silverman (2004)

This study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among monozygotic twins compared to siblings in a sample of 16 families. The study demonstrated significant aggregation of symptoms in twins. It also concluded that "the levels of clinical features seen in autism may be a result of mainly independent genetic traits."[13]

Ronald et al (2006)

An English twin study which found high heritability for autistic traits in a large group of 3,400 pairs of twins.[14]

The importance of sibling studies lies in contrasting their results to those of fraternal (DZ) twin studies, plus their sample sizes can be much larger. Environment sharing by siblings is presumably different enough to that of DZ twins to shed some light on the magnitude of environmental influence. This should even be true to some extent regarding the prenatal environment. Unfortunately DZ twin study findings have yielded a very large range of variance and are error prone because of the apparent low concordance and the fact that they typically look at a small number of DZ pairs. For example, in studies involving 10 DZ pairs, a concordance below 10% would be impossible to determine precisely.[How to reference and link to summary or text]

Bolton-Macdonald-Pickles-Rios-Goode-Crowson-Bailey-Rutter (1994)

This was a study of 99 autistic probands which found a 2.9% concordance for autism in siblings, and between 12.4% and 20.4% concordance for a "lesser variant" of autism.[15]

Hughes-Plumet-Leboyer (1999)

This was a study of 31 siblings of autistic children, 32 siblings of children with developmental delay, and 32 controls. It found that the siblings of autistic children, as a group, "showed superior spatial and verbal span, but a greater than expected number performed poorly on the set-shifting, planning, and verbal fluency tasks."[16]

Lauritsen-Pedersen-Mortensen (2005)

This study looked at "data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity." It found an overall prevalence rate of roughly 0.08%. Prevalence of autism in siblings of autistic children was found to be 1.76%. Prevalence of autism among siblings of children with Asperger's syndrome or PDD was found to be 1.04%. The risk was twice as high if the mother had been diagnosed with a psychiatric disorder. The study also found that "the risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age."[17]

This study looked at the personalities of parents of autistic children, using parents of children with Down's syndrome as controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive."[18]

Piven-Palmer-Jacobi-Childress-Arndt (1997)

This study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.[19]

Baron-Cohen-Bolton-Wheelwright-Scahill-Short-Mead-Smith (1998)

This study confirms the suspicion that autism occurs more often in families of physicists, engineers and scientists.[20] Other studies have yielded similar results.[21][22] Findings of this nature have led to the coinage of the term "geek syndrome".[23]

Happe-Briskman-Frith (2001)

This study examined brothers and parents of autistic boys. It looked into the phenotype in terms of one current cognitive theory of autism. The study raised the possibility that the broader autism phenotype may include a "cognitive style" (weak central coherence) that can confer information-processing advantages.[24]

This study showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.[25]

Constantino-Todd (2005)

This study focused on sub-threashold autistic traits in the general population. It found that correlation for social impairment or competence between parents and their children and between spouses is about 0.4.[26]

Ghaziuddin (2005)

This report examined the family psychiatric history of 58 subjects with Asperger's syndrome (AS) diagnosed according to DSM-IV criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia. Thirty five (60%) had a family history of depression. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.[27]

Some studies have suggested that the twinning process itself is a risk factor
in the development of autism, presumably due to perinatal factors.[28] At least one study shows no correlation between twinning and autism, however.[29] Higher risk among twins due to environmental factors would have significant
implications on twin studies.

Evidence has mounted indicating that clinical pictures that look like autism (phenocopies) may not be due to the same genetic liability. Examples are congenital blindness,[30] profound institutional privation,[31][32] and a number of conditions related to mental retardation.[33]

Which factors could be involved in the failure to find a 100% concordance in identical twins?

Is profound mental retardation a characteristic of the genotype or something totally independent?

Some researchers have speculated that what we currently refer to as "autism" may be a catch-all description for many yet unknown conditions with different genetic and/or environmental etiologies. This would appear to make the effort to find a genotype model a lot more difficult, and perhaps even pointless. Nevertheless, a number of genetic models have been proposed to try to explain the results of twin and sibling studies.

The original Mendelian model tried to explain observations using distinct genes existing in clearly dominant or recessive alleles. That would imply a recessive "autism gene" inherited from each of the parents. This kind of model is clearly too simple:[34]

It indicates that a sibling of an autistic individual should have 25% risk of having the autistic genotype, which is inconsistent with fraternal twin and sibling study results.

It would require several characteristic features of autism to be caused by a single allele at a single locus.

Further considerations for the 'autism gene model' of also show contradictory implications:

(a) only a small number of cases can be clearly linked to a possible genetic cause and these are often allele deletions;

(b) the majority of patients with autism do not marry and do not have offspring which should result in a decreased incidence of the presumed gene in the general population.

(c) the incidence of autism in the population has been increasing instead, making the likelihood of a single genetic cause extremely remote.

Reduced risk to relatives of probands and identical/fraternal twin ratios indicate that a multigene model is more likely to account for the autistic genotype. That is, at least 2 alleles would be involved, and most likely 3 to 5. Researchers have suggested models of 15 and even up to 100 genes.[How to reference and link to summary or text]

The fraternal twin results found by Ritvo et al (1985)[7] and the broader phenotype results of Bolton et al (1994)[15] suggest that a 2-gene model is plausible. Kolevzon et al (2004) proposed that the 3 characteristic symptoms of autism may be the result of 3 different alleles.[How to reference and link to summary or text] Data supports the multiple-locus hypothesis and also that a 3-loci model is the best fit.[35] Risch et al (1999) found results most compatible with a large number of loci (>= 15).[36]

Given the significant prevalence of autism, perhaps 0.1% for classic autism and at least 0.6% for a broader spectrum,[How to reference and link to summary or text] a multigene model has important implications. Since intelligence appears to be independent of the recognized characteristic symptoms of autism (and the diagnostic criteria) it is likely that many individuals are very autistic yet highly functional, allowing them to escape a diagnosis altogether.[How to reference and link to summary or text] So the prevalence of the autistic genotype may be considerably higher than thought. And if multiple alleles are part of the genotype, then each allele must have relatively high prevalence in the general population.[How to reference and link to summary or text]

A number of alleles have been shown to have strong linkage to the autism phenotype. In many cases the findings are inconclusive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of genotypes that are
manifested as the autism phenotype. At least some of the alleles associated with autism are fairly prevalent in the general population, which indicates they are not rare pathogenic mutations. This also presents some challenges in identifying all the rare allele combinations involved in the etiology of autism.

17q11.2 region, SERT (SLC6A4) locus

This gene locus has been associated with rigid-compulsive behaviors. Notably, it has also been associated with depression but only as a result of social adversity, although other studies have found no link.[39] Significant linkage in families with only affected males has been shown.[40][41] Researchers have also suggested that the gene contributes to hyperserotonemia.[42]

GABA receptor subunit genes

GABA is the primary inhibitory neurotransmitter of the human brain. Ma et al (2005) concluded that GABRA4 is involved in the etiology of autism, and that it potentially increases autism risk through interaction with GABRB1.[43] The GABRB3 gene has been associated with savant skills.[44]

Engrailed 2 (EN2)

Engrailed 2 is believed to be associated with cerebellar development. Benayed et al (2005) estimate that this gene contributes to as many as 40% of ASD cases, about twice the prevalence of the general population.[45] But at least one study has found no association.[46]

3q25-27 region

A number of studies have shown a significant linkage of autism and Asperger's syndrome with this locus.[47][48] The most prominent markers are in the vicinity of D3S3715 and D3S3037.[49]

7q21-q36 region, REELIN (RELN)

In adults, Reelinglycoprotein is believed to be involved in memory formation, neurotransmission, and synaptic plasticity. A number of studies have shown an association between the REELIN gene and autism,[50][51] but a couple of studies were unable to duplicate linkage findings.[52]

Dr. Patricia Rodier has identified a link between HOX genes and the development of the embryonic brain stem. In particular, two genes, HOXA1 and HOXB1, in transgenic 'knockout' mice, engineered so that these genes were absent from the genomes of the mice in question, exhibited very specific brain stem developmental differences from the norm, which were directly comparable to the brain stem differences discovered in a human brain stem originating from a diagnosed autistic patient.[56][verification needed]

Conciatori et al (2004) found an association of HOXA1 with increased head circumference.[57] A number of studies have found no association with autism.[58][59][60] The possibility remains that single allelic variants of the HOXA1 gene are insufficient alone to trigger the developmental events in the embryo now associated with autistic spectrum conditions. Tischfield et al published a paper which suggests that because HOXA1 is implicated in a wide range of developmental mechanisms, a model involving multiple allelic variants of HOXA1 in particular may provide useful insights into the heritability mechanisms involved.[61] Additionally, Ingram et al alighted upon additional possibilities in this arena.[62] Transgenic mouse studies indicate that there is redundancy spread across HOX genes that complicate the issue, and that complex interactions between these genes could play a role in determining whether or not a person inheriting the requisite combinations manifests an autistic spectum condition[63] - transgenic mice with mutations in both HOXA1 and HOXB1 exhibit far more profound developmental anomalies than those in which only one of the genes differs from the conserved 'norm'.

In Rodier's original work, teratogens are considered to play a part in addition, and that the possibility remains open for a range of teratogens to interact with the mechanisms controlled by these genes unfavourably (this has already been demonstrated using valproic acid, a known teratogen, in the mouse model).[How to reference and link to summary or text]

PRKCB1

Philippi et al (2005) found a strong association between this gene and autism. This is a recent finding that needs to be replicated.[64]

FOXP2

The FOXP2 gene is of interest because it is known to be associated with developmental language and speech deficits. An association to autism appears to be elusive, nonetheless.[65][66]

UBE3A

The UBE3A gene has been associated with Angelman syndrome. Samaco et al (2005) suggest reduced expression of UBE3A in autism, as is the case in Rett syndrome.[67] In any case, it appears that the role of UBE3A is limited.

Shank3/ProSAP2, 22q13 and Neuroligins

The gene called SHANK3 (also designated ProSAP2) regulates the structural organization of neurotranmsitter receptors in post-synaptic dendritic spines making it a key element in chemical binding crucial to nerve cell communication.[68] SHANK3 is also a binding partner of chromosome 22q13 (i.e. a specific section of Chromosome 22) and neuroligin proteins; deletions and mutations of SHANK3, 22q13 (i.e. a specific section of Chromosome 22) and genes encoding neuroligins have been found in some people with autism spectrum disorders.[69][70]

Mutations in the SHANK3 gene have been strongly associated with the Autism Spectrum Disorders.[71] If the SHANK3 gene is not adequately passed to a child from the parent (haploinsufficiency) there will possibly be significant neurological changes that are associated with yet another gene, 22q13, which interacts with SHANK3. Alteration or deletion of either will effect changes in the other.[72]

A deletion of a single copy of a gene on chromosome 22q13 has been correlated with global developmental delay, severely delayed speech or social communication disorders and moderate to profound delay of cognitive abilities. Behavior is described as "autistic-like" and includes high tolerance to pain and habitual chewing or mouthing[73] (see also 22q13 deletion syndrome). This appears to be connected to the fact that signal transmission between nerve cells is altered with the absence of 22q13.

SHANK3 proteins also interact with neuroligins at the synapses of the brain further complicating the widespread effects of changes at the genetic level and beyond.[74]
Neuroligin is a cell surface protein (homologous to acetylcholinesterase and other esterases) that binds to synaptic membranes.[75] Neuroligins organize postsynaptic membranes that function to transmit nerve cell messages (excitatory) and stop those transmissions (inhibitory);[76] In this way, neuroligins help to ensure signal transitions between nerve cells.[77] Neuroligins are also regulate the maturation of synapses and ensure there are sufficient receptor proteins on the synaptic membrane.

Though not present in all individuals with autism, these mutations hold potential to illustrate some of the genetic components of spectrum disorders.[78]

It is also known to play a key role in both normal and abnormal development, such as cancermetastases (hence the name MET). A mutation of the gene, rendering it less active, has been found to be common amongst children with autism.[80] Mutation in the MET gene demonstrably raises risk of autism by 2.27 times.[81][82]

neurexin 1

In February 2007, researchers in the Autism Genome Project (an international research team composed of 137 scientists in 50 institutions) reported possible implications in aberrations of a brain-development gene called neurexin 1 (located on chromosome 11) as a cause of some cases of autism.[83][84][85][86]DNA from over 1,600 families was analyzed in what was the largest-scale genome scan conducted in autism research at the time.

The objective of the study was to locate specific brain cells involved in autism to find regions in the genome linked to autism susceptibility genes. The focus of the research was CNVs, or “copy number variations." CNVs are extra or missing parts of genes. Each person does not actually have just an exact copy of genes from each parent. Each person also has occasional multiple copies of one or more genes or some genes are missing altogether. The research team attempted to locate CNVs when they scanned the DNA of the 1,600 families.

Neurexin 1 is one of the genes that may be involved in communication between nerve cells (neurons). Neurexin 1 and other genes like it are very important in determining how the brain is connected from cell to cell, and in the chemical transmission of information between nerve cells, These genes are particularly active very early in brain development, either in utero or in the first months or couple of years of life.". In some families their autistic child had only one copy of the neurexin 1 gene.

Besides actually locating yet another possible genetic influence (the findings were statistically insignificant), the research also reinforced the theory that autism involves many forms of genetic variations.

Others

There is a large number of other candidate loci which either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes.[87][88][89]

Monozygotic twin studies show that genetic predisposition to autism has its limitations. For example, it would appear that about 40% of diagnosed individuals originally had a 50/50 chance of being considered high functioning. About 4% to 10% had a 50/50 chance of escaping a diagnosis altogether. This has led researchers to postulate that any number of environmental factors may influence the development of persons genetically predisposed to autism; and that by locating the environmental
triggers involved it might be possible to find ways to improve the outcome of biologically autistic individuals.

But not everyone agrees regarding the magnitude and nature of environmental influence. Critics of environmental theories of autism point out the following:

If environmental factors played a major role, significantly divergent findings between fraternal twin and sibling studies would be expected.

Evaluation margin of error and temporary behavioral differences in twins should be taken into account.

A minority of cases characterized as "autism" could be environmentally-caused phenocopies of the genotype, and should not be called "autism" once identified.

Developmental and behavioral differences have been observed in identical twins with conditions that have a well-established genetic etiology.[91][92][93][94][95]

The search for environmental triggers has been mostly focused on trying to find a cause for a rapid increase in the reported prevalence of autism in recent decades. The prevalence increase would appear to implicate recent changes in human lifestyle, but there is considerable disagreement as to whether the number of cases is actually increasing.[How to reference and link to summary or text]

A recent finding of an anomaly in the apparent prevalence of autism among the Amish would seem to support the notion that modern lifestyle has to do with the prevalence increase.[96][verification needed] The Amish, however, are a very isolated community, genetically as well, so this finding does not necessarily shed any light on heritability without further study. It should be stressed that the
Amish finding is very preliminary.

Many of the environmental trigger theories are based on anecdotal accounts of regressive autism observed after a particular occurrence, particularly vaccination.

The exponential increase of level one autism diagnoses, the least ambiguous diagnostic category, has led some researchers to hypothesize that the environmental trigger is quite literally an "epidemic", involving the exponential spread of an infectious disease agent such as virus or bacteria. One theory is of an intestinal virus disrupting the mucosa and allowing neurotoxins to enter the bloodstream.[97] Another is that the Borna virus -- suggested to be involved in schizophrenia, although some recent studies have not borne this out[98] -- is triggering autism among the genetically susceptible.[99] Another hypothetical trigger is the herpes virus.[100]

Some parents and researchers have alleged that heavy metal poisoning, particularly that involving mercury, results in symptoms similar to those of autism. Despite this belief having been refuted,[101] they propose that one of the following could be the case:

One of the liabilities of the autism genotype could be markedly reduced tolerance to heavy metal toxicity.

Mercury toxicity could simply amplify the symptoms of autism.

Some studies have implicated mercury and other metals used in dental fillings as playing a role in the etiology of autism.[102][103] A theory that is very popular among parents is that vaccines that use thimerosal as a preservative are to blame for the prevalence increase in cases of autism.

Nevertheless, the link is inconclusive. Ip et al (2004) compared hair and blood mercury levels in autistic children with those of non-autistic controls and found a 10% increase in blood and hair mercury levels of autistic children, which is not statistically significant.[104] Their results are questionable in that they chose to analyze mercury levels in children who were already diagnosed with autism.[How to reference and link to summary or text] If exposure to mercury at a particular stage in a child's development were to make that child more succeptable to Autism, studying children who already have autism will not find this link. Furthermore, their study looks at children with an average age of approximately 7 years, whereas early onset autism (thought to be linked ot thimerosal) has "onset prior to age 3 years" (DSM-IV). A more appropriate study would involve mercury levels in children prior to age 3 years.[How to reference and link to summary or text]

Madsen et al (2003) found no reduction in the prevalence of autism in Denmark after MMR Vaccination was phased out.[105] However, this work has serious ommisions in that they failed to look at vaccines containing thimerosal and did not differentiate beteween regressive autism (thought to be linked to MMR) and early onset autism (thought to be linked to thimerosal).

Individuals diagnosed with ASD have repeatedly been shown to have significantly higher incidence of prenatal and perinatal complications.[106][107] This link does not demonstrate a causal relationship, however. Researchers have suggested that birth complicatons are the result of genetic predisposition.

Some studies have shown that autistic children are affected by stressful events more than their non-autistic counterparts.[108][109] (But a subset of them seem to be less affected by psychosocial stress in particular.[110])

Since the 1950s up to the 1970s it was believed that autism was the result of the faulty environment provided by uncaring "refrigerator" mothers, a theory that went largely unchallenged by psychologists at the time. This theory is discredited now, along with its main champion, Bruno Bettelheim.

The Folstein-Rutter (1977) twin study[How to reference and link to summary or text] is credited with shifting the focus from psychological factors to genetics. But in retrospect, it did not prevent other environmental theories from arising.

It was also observed that many mothers of autistic children were very loving. In cases where social interaction was found to be impaired between mother and child, it has been proposed this is simply due to social deficits in the child. Today, parent-blame theories are considered offensive. Hence, this is a sensitive topic, perhaps the reason it has not been studied in recent decades.

There has been a general drastic shift in the focus of psychiatry in recent history, from theories based on early childhood psychological trauma to genetic and other neurological causes for disorders. Additionally, comparisons of twins reared apart with those reared together have shown that the shared environment (i.e. the family) is not as influential as the non-shared environment.

This is not to say that parenting is irrelevant. Some case reports have shown that profound institutional privation can result in quasi-autistic symptoms.[116] Children genetically predisposed to autism are likely not immune to the effects of psychological privation, and in fact could be more sensitive to them. This also has some implications regarding institutionalization of autistic individuals, a practice still common today. The specific forms of institutional privation involved are unknown (though it is known that it is not nutritional privation). This information could presumably shed some light on subtle ways to affect the outcome of autistic individuals.